Process for the preparation of a cyano-isobenzofuran

Abstract

A process for the preparation of citalopram and the pharmaceutically acceptable salts therof is disclosed by reacting 5-cyanophthalide with a 4-fluorophenyl magnesium halide, reducing the 3-hydroxymethyl-4-(4-fluorobenzoyl)benzonitrile with an agent reducing ketones to alcohols, submitting the thus-obtained 3-hydroxymethyl-4-[(4-fluorophenyl)hydroxymethyl)benzonitrile to a cyclization reaction to give 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile without 1,1-bis(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile and treating 1,1-bis(4 fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile with a 3-(dimetylamino)propyl halide in the presence of a base.

The invention claimed is: 
     
       1. A process for the preparation of pure 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile which comprises:
 (a) reacting 5-cyanophthalide with a 4-fluorophenylmagnesium halide; 
 (b) treating the mixture thus obtained, containing the 3-hydroxymethyl-4-(4-fluorobenzoyl)benzonitrile and the 3-hydroxymethyl-4-[bis-(4-fluorophenyl)hydroxymethyl]benzonitrile with a reducing agent of ketones to alcohols; 
 (c) submitting the mixture thus obtained, containing the 3-hydroxymethyl-4-[(4-fluorophenyl)hydroxymethyl]benzonitrile (C) and the 3-hydroxymethyl-4-[bis-(4-fluorophenyl)hydroxymethyl]benzonitrile to a cyclization reaction and isolating a mixture containing the 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile (B) and the 1,1-bis(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile; and 
 (d) treating the mixture thus obtained with a solvent capable of dissolving the 1,1-bis(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile and in which the 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile (B) is insoluble and recovering the pure 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile (B), wherein said solvent is isopropanol or methyl-t-butylether. 
 
     
     
       2. A process according to  claim 1 , wherein, in step (b) the reduction is carried out with NaBH 4  in water and sodium hydroxide. 
     
     
       3. A process according to  claim 1 , wherein, in step (c), the cyclization is carried out with phosphoric acid in a biphasic water/organic solvent medium. 
     
     
       4. A process according to  claim 3 , wherein said biphasic medium consists of water/ethyl acetate. 
     
     
       5. A process according to any one of  claims 1  to  4 , wherein, in step (d), isopropanol or methyl-t-butylether is used as a solvent capable of dissolving the 1,1-bis(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile and in which the 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile (B) is insoluble. 
     
     
       6. A process according to any one of  claims 1  to  5 , wherein the 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile (B) is further reacted with a 3-(dimetylamino)propyl halide in the presence of a basic condensing agent and citalopram is isolated as free base or as a pharmaceutically acceptable salt thereof. 
     
     
       7. A process according to  claim 6 , wherein the chloride is used as an halide, sodium hydride is used as a basic condensing agent and the condensation is carried out in dimethylsulfoxide. 
     
     
       8. A process for the preparation of citalopram or of a pharmaceutically acceptable salt thereof, which comprises:
 (a) reacting 5-cyanophthalide with a 4-fluorophenylmagnesium halide; 
 (b) treating the mixture thus obtained, containing the 3-hydroxymethyl-4-(4-fluorobenzoyl)benzonitrile and the 3-hydroxymethyl-4-[bis-(4fluorophenyl)hydroxymethyl]benzonitrile with a reducing agent of ketones to alcohols; 
 (c) submitting the mixture thus obtained, containing the 3-hydroxymethyl-4-[(4-fluorophenyl)hydroxymethyl]benzonitrile (C) and the 3-hydroxymethyl-4-[bis-(4-fluorophenyl)hydroxymethyl]benzonitrile to a cyclization reaction and isolating a mixture containing the 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile (B) and the 1,1-bis(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile; 
 (d) treating the mixture thus obtained with a solvent capable of dissolving the 1,1-bis(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile and in which the 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile (B) is insoluble and recovering the pure 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile (B), wherein said solvent is isopropanol or methyl-t-butylether; 
 (e) treating the pure 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile (B) with a 3-(dimethylamino)propyl halide in the presence of a basic condensing agent and isolating citalopram as free base or as a pharmaceutically acceptable salt thereof. 
 
     
     
       9. A process according to  claim 8 , wherein, in step (b) the reduction is carried out with NaBH 4  in water and sodium hydroxide. 
     
     
       10. A process according to  claim 8 , wherein, in step (c), the cyclization is carried out with phosphoric acid in a biphasic water/organic solvent medium. 
     
     
       11. A process according to  claim 10 , wherein said biphasic medium consists of water/ethyl acetate. 
     
     
       12. A process according to any one of  claims 8  to  11 , wherein, in step (d), isopropanol or methyl-t-butylether is used as a solvent capable of dissolving the 1,1-bis(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile and in which the 1-(4fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile (B) is insoluble.